Dear Editor,
We recently authored an editorial commenting on the important study by Huang et al. and were delighted to receive Dr. Huang and Dr. Nguyen’s thoughtful correspondence [
1-
3]. In our editorial, we highlighted the pronounced impact of type 2 diabetes mellitus (T2DM) on the long-term outcomes of chronic hepatitis B (CHB) patients despite effective antiviral therapy, and emphasized that diabetes management should be integrated into CHB care. Huang et al.’s original findings indeed reinforced that among metabolic comorbidities, diabetes stands out as a distinct and potent risk factor. In their large multicenter cohort, the presence of diabetes was associated with significantly higher cumulative incidence of cirrhosis, hepatocellular carcinoma (HCC), and overall mortality despite nucleos(t)ide analogue (NA) treatment [
3]. This underscores our shared message that T2DM, more than other metabolic components or the number of metabolic syndrome features, is a key driver of adverse outcomes in NA-treated CHB.
Notably, emerging clinical guidelines increasingly acknowledge diabetes as a major risk factor for HCC in CHB. The 2024 World Health Organization guidelines for HBV treatment now include diabetes as a criterion for initiating antiviral therapy, recommending treatment for CHB patients with HBV DNA ≥2,000 IU/mL and coexistent diabetes even in the absence of significant fibrosis [
2]. Indeed, diabetes is now a component of several validated HCC risk models, such as REAL-B, CAMD and AFDA [
4-
6]. This paradigm shift reflects a growing body of evidence linking T2DM with adverse liver outcomes, including HCC, and supports its integration into both treatment algorithms and HCC surveillance strategies.
We also acknowledge the insightful discussion by Dr. Huang and Dr. Nguyen regarding the complex tripartite relationship among diabetes, hepatic steatosis, and CHB progression. Their study observed that, in contrast to diabetes, the presence of hepatic steatosis was not associated with worse outcomes – in fact, fatty liver was linked to a lower risk of cirrhosis and HCC in their CHB cohort [
3].
However, this growing recognition of diabetes as a key risk factor in CHB management brings attention to a more nuanced and unresolved question: what is the role of hepatic steatosis in CHB progression and hepatocarcinogenesis? Unlike the consistent association observed with diabetes, findings regarding hepatic steatosis have been conflicting. Some cohort studies, including those by Huang et al., suggest a potential protective role of hepatic steatosis in CHB patients, showing an inverse association with the risks of cirrhosis and HCC [
7]. Conversely, a recent metaanalysis including over 68,000 CHB patients reported that hepatic steatosis was associated with a significantly increased risk of both HCC and cirrhosis, though this association was not observed in subgroups receiving nucleos(t) ide analogue therapy [
8]. These inconsistencies underscore the complex and context-dependent nature of hepatic steatosis in CHB. Its prognostic impact appears to vary according to the presence of metabolic dysfunction, antiviral treatment status, and method of steatosis assessment. Moreover, hepatic steatosis may influence liver-related outcomes not only directly but also indirectly by promoting insulin resistance and incident diabetes—thereby amplifying HCC risk via a metabolic cascade.
Ultimately, advancing our understanding of this “tripartite axis” linking HBV, hepatic steatosis, and diabetes will be instrumental in developing precision HCC surveillance strategies and personalized interventions for CHB patients. Further research is warranted to elucidate the mechanistic links and causal pathways connecting these conditions, clarifying why steatosis might attenuate liver injury in CHB while diabetes exacerbates it. We strongly advocate for an integrated, multidisciplinary approach to CHB management that extends beyond viral suppression to include proactive prevention, detection, and treatment of metabolic diseases— especially diabetes. This collaborative care model, involving primary care physicians, endocrinologists, and nutritionists, addresses the comprehensive needs of patients living with CHB and metabolic dysfunction, ultimately reducing cirrhosis and HCC incidence while improving longterm prognosis. We appreciate Dr. Huang and Dr. Nguyen’s valuable correspondence and shared commitment to advancing care for CHB patients amidst today’s metabolic health challenges.
FOOTNOTES
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Authors’ contribution
All authors were responsible for the conceptualization, interpretation of data, drafting, and critical revision of the manuscript.
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Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
REFERENCES
- 1. Jang H, Kim W. Type 2 diabetes as a key metabolic risk factor for adverse outcomes in nucleos(t)ide analogue-treated chronic hepatitis B. Clin Mol Hepatol 2026;32:426-428.
- 2. Huang R, Nguyen MH. Correspondence to editorial 2 on “Impacts of metabolic syndrome diseases on long-term outcomes of chronic hepatitis B patients treated with nucleos(t)ide analogues”. Clin Mol Hepatol 2026;32:e85-e86.
- 3. Huang R, Jun DW, Toyoda H, Hsu YC, Trinh H, Nozaki A, et al. Impacts of metabolic syndrome diseases on long-term outcomes of chronic hepatitis B patients treated with nucleos(t)ide analogues. Clin Mol Hepatol 2025;31:1003-1017.
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- 7. Huang SC, Su TH, Tseng TC, Chen CL, Hsu SJ, Liao SH, et al. Distinct effects of hepatic steatosis and metabolic dysfunction on the risk of hepatocellular carcinoma in chronic hepatitis B. Hepatol Int 2023;17:1139-1149.
- 8. Mao X, Cheung KS, Peng C, Mak LY, Cheng HM, Fung J, et al. Steatosis, HBV-related HCC, cirrhosis, and HBsAg seroclearance: A systematic review and meta-analysis. Hepatology 2023;77:1735-1745.
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